ICR WHITE PAPER 003
THE FIVE LAYERS OF HUMAN REGULATION
A Multilevel Map for Organizing Context, Neural Regulation,Resource Coordination, Tissue Organization, and Cellular Function
David FischerInstitute for Coherence and Regulation (ICR)Knightdale, North Carolina, USASeptember 2026 | Publication Version 1.0
Recommended citationFischer, D. (2026). The Five Layers of Human Regulation: A Multilevel Map for Organizing Context, Neural Regulation, Resource Coordination, Tissue Organization, and Cellular Function. ICR White Paper 003 (Publication Version 1.0). Institute for Coherence and Regulation.
DOI: 10.5281/zenodo.22708644
Abstract
The Coherence & Regulation Framework (CRF) organizes human regulatory influences into five analytically distinct but reciprocally coupled layers: Meaning & Context; Nervous System Regulation; Metabolic & Endocrine Coordination; Structural & Tissue Organization; and Cellular & Biochemical Function. The five-layer architecture is not proposed as a new biological taxonomy or as a unidirectional causal hierarchy. It is an organizing map intended to support interdisciplinary reasoning, measurement, and hypothesis formation while preserving evidentiary boundaries between psychological, physiological, mechanical, and molecular claims. This paper defines each layer, identifies established scientific literatures that support components of the architecture, describes candidate pathways connecting adjacent and nonadjacent layers, proposes measurement strategies, and specifies falsifiable tests of whether the five-layer organization adds value beyond simpler models. Existing literature demonstrates that contextual appraisal can engage neural-autonomic and endocrine stress systems; interoceptive and allostatic processes connect central control with bodily state; circadian clocks coordinate metabolic activity across cells and tissues; and mechanotransduction links tissue mechanics with biochemical signaling. These findings support cross-scale coupling but do not validate CRF as a whole. The framework therefore requires prospective multidomain research, explicit comparison with alternative taxonomies, and independent replication.
Keywords: multilevel regulation; biopsychosocial model; allostasis; interoception; autonomic regulation; circadian metabolism; mechanotransduction; systems biology; adaptive capacity; coherence
1. Purpose and Scientific Status
ICR White Paper 003 establishes the canonical five-layer architecture of CRF. Its purpose is to provide a stable map for asking where an observation belongs, what can legitimately be inferred from it, what additional measurements would be required to move to another level of explanation, and how interactions among levels can be studied.
The architecture is conceptual. Each layer contains processes already studied by established disciplines, but the particular five-layer arrangement is an ICR synthesis. Existing evidence can support a relationship contained within the map without proving that five layers are optimal, exhaustive, or uniquely correct.
Accordingly, the scientific question is not whether the five layers sound plausible. The question is whether organizing variables this way improves conceptual clarity, measurement, prediction, or interdisciplinary communication compared with established alternatives.
2. Canonical Architecture
Layer
Primary domain
Central regulatory question
Examples of measurement
1. Meaning & Context
Appraisal, expectation, safety/threat, social and environmental context
What does the organism infer the situation requires?
Validated stress/appraisal measures, perceived safety, social context, ecological momentary assessment
2. Nervous System Regulation
Central/autonomic state regulation, interoception, arousal, neuroendocrine control
Can state shift appropriately with demand and recovery?
Heart rate, selected HRV metrics, blood pressure, respiration, electrodermal activity, sleep, validated scales
3. Metabolic & Endocrine Coordination
Resource allocation, endocrine signaling, circadian and feeding-fasting timing
Are resources available and temporally coordinated with demand?
Sleep/activity timing, meal timing, glucose or endocrine measures when appropriate, fatigue/energy measures
4. Structural & Tissue Organization
Movement, breathing mechanics, tissue loading, ECM, circulation, sensorimotor feedback
Does physical organization support efficient function under demand?
Function, movement, strength, gait, respiratory mechanics, pain measures, tissue mechanics
5. Cellular & Biochemical Function
Cell signaling, metabolism, immune activity, redox, repair, gene expression
Can cells and tissues execute required functions under present conditions?
Laboratory biomarkers, molecular assays, cellular measures, imaging or tissue-specific measures
3. Rules for Interpreting the Layers
The layers are analytic categories, not anatomical compartments.
The numerical order is representational and does not imply top-down primacy.
Influence is expected to be bidirectional and time-dependent.
A variable should be described at the level actually measured.
No single layer is sufficient to explain every health outcome.
CRF does not require that every study measure all five layers.
An intervention placed in a layer is not validated merely by being included in the framework.
The architecture must remain open to revision if another organization explains or predicts data better.
These rules are central to scientific use of CRF. Without them, a multilevel model can deteriorate into an unfalsifiable claim that every observation reflects every level. CRF instead requires investigators to specify which variable was measured, the proposed direction of influence, the expected latency, plausible confounders, and the evidence required to support movement from one layer to another.
4. Layer 1 — Meaning & Context
4.1 Definition
Meaning & Context includes appraisal, expectation, perceived safety or threat, controllability, social relationship, role, purpose, prior learning, environmental predictability, cultural interpretation, and the behavioral options an individual believes are available. The layer asks how the present situation is represented and what demand that representation implies.
4.2 Scientific basis
The inclusion of context is consistent with established stress neurobiology. Neural regulation of stress responses involves brainstem and hypothalamic pathways for systemic challenges as well as limbic structures involved in psychological stress. Medial prefrontal, hippocampal, and amygdala-related circuits can influence autonomic and hypothalamic-pituitary-adrenal responses. This provides a biological route by which appraisal and learned context can influence downstream physiology.
Contextual-effect and placebo research further demonstrates that expectation and learning can alter pain and other physiological outcomes through identifiable neural processes. CRF uses this literature conservatively: it establishes that meaning and context can be biologically relevant, not that thought can override disease or directly determine molecular outcomes.
4.3 Candidate measures
Perceived Stress Scale or other validated stress measures
Perceived controllability and predictability
Validated social safety or social support measures
Expectation and treatment-belief measures in intervention studies
Ecological momentary assessment of context and appraisal
Environmental stimulation, workload, caregiving, or social-demand exposure
4.4 Boundary
A person's narrative, belief, or perceived stress cannot establish inflammation, autonomic disease, endocrine dysfunction, mitochondrial impairment, or any other unmeasured biological condition. Layer 1 findings remain Layer 1 findings until downstream variables are measured.
5. Layer 2 — Nervous System Regulation
5.1 Definition
Nervous System Regulation includes central and autonomic state regulation, arousal, sensory processing, interoception, attention, state transitions, neuroendocrine control, and the timing of mobilization and recovery. Its central concern is not simply whether activation is high or low, but whether activation is appropriate to context and whether the system can transition efficiently.
5.2 Allostasis and interoception
Contemporary allostatic models treat the brain as an anticipatory regulator of bodily needs. Control-theoretic work on interoception proposes that internal sensory information provides feedback for allostatic regulation. This supports a CRF view in which nervous-system regulation is neither isolated from the body nor reducible to conscious experience.
5.3 Autonomic integration
Neurovisceral-integration research links prefrontal, limbic, brainstem, and autonomic processes and has motivated the use of cardiac autonomic dynamics in research on cognitive and emotional regulation. CRF does not equate a particular HRV value with coherence. Heart-rate variability is influenced by respiration, posture, age, fitness, medication, measurement duration, and other factors and should be interpreted according to a prespecified question.
5.4 Candidate measures
Heart rate and selected HRV measures under standardized conditions
Blood pressure and cardiovascular reactivity
Respiratory rate and respiratory pattern
Electrodermal activity or pupillometry in appropriate studies
Sleep duration, timing, continuity, and validated sleep measures
Cortisol or other neuroendocrine measures when protocol and interpretation are appropriate
Response and recovery trajectories after standardized perturbation
5.5 Boundary
Difficulty relaxing is a reportable experience, not by itself a diagnosis of autonomic dysfunction. Likewise, a wearable-derived metric should not be promoted as a comprehensive nervous-system score without validation.
6. Layer 3 — Metabolic & Endocrine Coordination
6.1 Definition
Metabolic & Endocrine Coordination includes resource availability, substrate use, endocrine signaling, circadian organization, feeding-fasting timing, and energetic support for adaptation and recovery. The layer asks whether resources and signals are available in appropriate amounts and at appropriate times.
6.2 Circadian coordination as a model system
Circadian physiology provides one of the clearest established examples of multiscale temporal coordination. Cell-autonomous clocks interact with light-dark and feeding-fasting cycles, while secreted signals communicate timing among cells and tissues. A large proportion of mammalian genes show daily rhythmic expression, and temporal organization helps coordinate energy use and segregate processes that should not occur simultaneously.
This literature illustrates a central CRF principle: regulation is not defined only by the magnitude of a variable. Timing and phase relationships can matter. It does not follow that every metabolic complaint is caused by circadian disruption.
6.3 Candidate measures
Sleep-wake and activity timing
Meal and fasting timing
Glucose dynamics where clinically/research appropriate
Selected endocrine markers under standardized collection conditions
Energy expenditure or activity measures
Validated fatigue and energy measures
Circadian phase markers in research settings
6.4 Boundary
Subjective low energy does not establish metabolic, thyroid, adrenal, mitochondrial, or endocrine pathology. Clinical abnormalities require appropriate clinical measurement and interpretation.
7. Layer 4 — Structural & Tissue Organization
7.1 Definition
Structural & Tissue Organization includes movement, posture as task-specific organization, breathing mechanics, tissue loading, extracellular matrix properties, circulation, local mechanical constraints, and sensorimotor feedback. The layer asks how physical organization supports or constrains function under current demand.
7.2 Mechanotransduction
Mechanotransduction provides a strong molecular basis for including tissue mechanics in a regulatory model. Cells sense mechanical features of the extracellular matrix through integrins, cytoskeletal structures, and associated signaling systems; cells also remodel the matrix. This creates reciprocal cell-matrix regulation rather than a passive scaffold.
The existence of mechanotransduction does not validate broad claims that posture, fascia, alignment, or mechanical manipulation causes or cures systemic disease. CRF uses mechanobiology to justify a measurable interface between mechanical conditions and cellular signaling, not to erase the need for condition-specific evidence.
7.3 Candidate measures
Task-specific movement and functional performance
Strength, endurance, gait, balance, or range of motion
Breathing mechanics and respiratory movement where relevant
Validated pain and disability instruments
Tissue stiffness or mechanical properties in research settings
Imaging or licensed clinical assessment when indicated
7.4 Boundary
A structural observation should not be converted into a biochemical diagnosis. Conversely, molecular pathology can alter tissue properties and function, so Layer 4 must be treated as bidirectional with Layer 5.
8. Layer 5 — Cellular & Biochemical Function
8.1 Definition
Cellular & Biochemical Function includes cell signaling, metabolism, mitochondrial processes, redox biology, immune activity, gene expression, membrane processes, repair, extracellular signaling, and molecular maintenance. This layer anchors the framework in directly measurable biological processes.
8.2 Why Layer 5 is an evidentiary boundary
Many wellness narratives move too quickly from subjective outcomes to molecular mechanisms. CRF explicitly prohibits that inference. Feeling calmer, sleeping better, reporting less pain, or showing a change in heart rate may be meaningful outcomes, but they do not demonstrate altered gene expression, immune normalization, mitochondrial repair, detoxification, or cellular regeneration.
8.3 Candidate measures
Condition-specific laboratory biomarkers
Inflammatory or immune markers selected for a defined hypothesis
Metabolomic, transcriptomic, proteomic, or genomic measures in appropriate research
Cellular assays or tissue sampling where ethically and scientifically justified
Validated clinical laboratory measures interpreted within scope
8.4 Boundary
Layer 5 claims require Layer 5 evidence. This is one of the most important safeguards in the entire CRF architecture.
9. Cross-Layer Coupling
The five layers become scientifically useful only if their relationships can be specified. CRF rejects the phrase 'everything is connected' as insufficient. A valid cross-layer proposition should state a measurable source variable, a measurable target variable, direction, time scale, mechanism or candidate pathway, and relevant competing explanations.
Connection
Established/plausible pathway
Example hypothesis
Primary caution
1 → 2
Appraisal/limbic influence on autonomic and HPA regulation
Higher perceived uncontrollability predicts slower autonomic recovery after a standardized stressor
Confounding by prior health, sleep, medication, and exposure
2 → 1
Interoceptive and arousal signals influence attention and appraisal
Persistent bodily arousal predicts higher subsequent threat appraisal within person
Reverse causality and shared causes
2 ↔ 3
Autonomic/neuroendocrine regulation coordinates metabolic resources
Stress-response dynamics predict short-term metabolic changes
Population and protocol dependence
3 ↔ 5
Circadian and metabolic signaling coordinate cellular activity
Circadian misalignment predicts altered metabolic/cellular markers
Do not generalize from animal to human outcomes without evidence
4 ↔ 5
Mechanotransduction and ECM remodeling
Defined mechanical loading alters specified cellular signaling or tissue remodeling
Effect is tissue- and dose-specific
1 ↔ 4
Pain, threat, expectation, movement and protective behavior interact
Threat expectation changes movement strategy during a standardized task
Psychological association does not negate tissue pathology
10. Why Five Layers Rather Than Three or Ten?
The five-layer architecture is a pragmatic compromise. Three broad biopsychosocial categories can be too coarse for distinguishing neural, metabolic, mechanical, and cellular claims. A much larger taxonomy may become difficult to use consistently. CRF separates domains when they involve materially different measurement methods, mechanisms, and scope boundaries.
This rationale remains hypothetical. Factor analysis, construct mapping, expert consensus, predictive modeling, and comparison with alternative architectures should test whether five layers are empirically useful. It is possible that future evidence will support merging layers, subdividing them, or using a nonhierarchical network representation.
11. Measurement Principles
Measure only the layers required by the hypothesis; completeness is not a virtue if measurement quality declines.
Prefer validated instruments and standardized physiological methods.
Use repeated measures when studying regulation, transition, variability, or recovery.
Distinguish state, trait, exposure, mediator, and outcome variables.
Predefine which layer each variable represents and acknowledge variables that legitimately span layers.
Do not create a global coherence score until its components show reliability and validity.
Compare multidomain models against simpler baselines and established constructs.
Report null, mixed, and adverse findings.
12. Falsifiable Hypotheses
H1. A prespecified model containing variables from at least three CRF layers will predict selected recovery outcomes better than a matched single-layer model in held-out data.
H2. Layer 1 contextual measures will explain variance in Layer 2 stress-response or recovery measures after relevant baseline covariates are controlled.
H3. Layer 2 recovery dynamics will predict subsequent Layer 1 perceived capacity or Layer 3 functional-energy outcomes within person.
H4. Circadian alignment variables in Layer 3 will predict recovery dynamics independently of total sleep duration in defined populations.
H5. Layer 4 mechanical variables will predict specified Layer 5 responses only under defined tissue, load, and time conditions rather than universally.
H6. The five-layer organization will demonstrate useful discriminant validity; if variables cannot be assigned with acceptable conceptual consistency, the architecture should be revised.
H7. Cross-layer coupling strength will vary with context and baseline state rather than remain fixed.
H8. Multidomain prediction gains will persist after correction for model complexity; otherwise the added layers do not justify themselves.
H9. Independent researchers using the canonical definitions will classify variables into the five layers with acceptable agreement.
H10. If alternative architectures consistently outperform the five-layer model in explanation, prediction, and usability, CRF should adopt the superior organization.
13. Proposed Validation Program
Phase 1 should be conceptual validation: independent experts from physiology, psychology, neuroscience, endocrinology, rehabilitation, and cell biology map representative variables to the five layers and identify ambiguities. Inter-rater agreement and qualitative critique should be published.
Phase 2 should test measurement feasibility in a repeated-measures observational cohort. The goal is not to prove CRF but to learn which variables are stable, responsive, redundant, or impractical.
Phase 3 should use standardized perturbation-recovery designs to test directional cross-layer hypotheses. Phase 4 should compare CRF models with established alternatives and simpler statistical models. Phase 5 should involve independent replication and, only after adequate validation, intervention-selection studies.
14. Application to ICR Practice and Education
In education, the five layers can teach practitioners to separate observation from inference. A client may report high stress and poor sleep (Layers 1 and 2), low energy (subjective outcome relevant to Layer 3), and muscular tension (Layer 4). Those observations do not establish inflammation, mitochondrial dysfunction, hormonal imbalance, or other Layer 5 pathology.
In wellness-program evaluation, the architecture can organize outcomes without converting them into medical claims. If a program improves perceived stress and ability to relax, those outcomes should be reported directly. If a study also measures sleep, autonomic recovery, metabolic markers, function, or biomarkers, each result can be located within the architecture and interpreted at its measured level.
The architecture is modality-agnostic. Coherence-Based Reiki, PEMF, light-based wellness exposure, frequency-based systems, structured rest, exercise, psychotherapy, medication, and other inputs do not become scientifically validated because they can be placed on the map. Each requires its own evidence and scope analysis.
15. Limitations
The five layers are broad and overlap. Nervous-system and endocrine processes are deeply coupled; structural and cellular processes are inseparable at tissue scale; meaning is instantiated biologically; and social context can alter every other layer through multiple pathways. The map simplifies this complexity and can therefore mislead if treated literally.
A second limitation is construct ownership. CRF synthesizes established domains and cannot claim discovery of the underlying physiology. The potentially original contribution is the particular architecture, canonical terminology, and hypotheses generated from it.
Third, multilevel models can become statistically overfit. Adding more variables almost always increases apparent explanatory power in-sample. CRF therefore requires held-out prediction, correction for complexity, and comparison with simpler models.
Fourth, evidence strength is uneven across proposed connections. Some pathways, such as circadian-metabolic coordination and cell-matrix mechanotransduction, have strong mechanistic foundations. Other proposed cross-layer relationships may be context-specific or weak. The framework should represent that unevenness rather than imply equal certainty.
16. Falsification and Revision Criteria
The five-layer architecture should be revised if independent experts cannot use it consistently; if its categories do not show useful discriminant validity; if cross-layer hypotheses repeatedly fail; if simpler established models perform as well or better; or if additional complexity does not improve prediction, measurement, or communication.
Revision is not failure. A version-controlled conceptual framework should become more precise as evidence accumulates. The Institute should preserve prior versions so that original predictions and later changes remain transparent.
17. Harmonization With WP-001 and the Unified Model
The five-layer architecture is the canonical organizing map used by WP-001 and WP-025. The layers describe where a variable is being observed; the Unified Model describes how measured variables may participate in a dynamic sequence involving context, demand, response, timing, flexibility, coordination, output, cost, compensation, recovery, reserve, and subsequent adaptive capacity.
The layers and the dynamic constructs should not be conflated. Regulatory Load, Regulatory Timing, Compensation, Recovery Dynamics, and Regulatory Drift are not additional layers. They are relationships or trajectories that can be studied within and across the five layers.
18. Comparison With Existing Multilevel Frameworks
Multilevel organization is not unique to CRF. NIH-associated health-science work has long described interdependent social/environmental, behavioral/psychological, organ-system, cellular, and molecular levels of analysis. Contemporary integrative physiology also continues to develop multilevel and multidomain frameworks. The CRF contribution, if any, must therefore lie in the usefulness of its particular layer boundaries, its coupling rules, and its integration with dynamic constructs—not in the generic idea that human function spans levels.
This comparison creates an explicit novelty test: if established multilevel frameworks organize the same research questions equally well or better, ICR should adopt or cite those frameworks rather than claim unnecessary originality.
19. Layer Assignment Decision Rule
Assign a variable according to what the measurement directly represents, not according to an assumed upstream cause or downstream consequence. When a measure genuinely spans domains, state that explicitly rather than forcing artificial exclusivity.
Perceived threat, meaning, expectation, or social context → Layer 1.
Heart rate, autonomic indices, neural activity, sensory or state-regulation measures → Layer 2 when that is the construct actually measured.
Direct metabolic or endocrine variables → Layer 3.
Movement, mechanical loading, tissue-level functional organization, or task biomechanics → Layer 4.
Direct molecular, cellular, biochemical, gene-expression, or assay variables → Layer 5.
20. Cross-Layer Evidence Standard
A cross-layer statement becomes stronger in stages: co-occurrence → statistical association → temporal ordering → intervention sensitivity → direct mechanistic evidence. Researchers should name the evidence level rather than using a generic phrase such as “the layers are connected.”
Stronger coupling is not automatically healthier. Perfect synchrony is not the CRF definition of coherence. Different processes can coordinate through lagged, reciprocal, inhibitory, phase-specific, or context-dependent relationships.
21. Five-Layer Measurement Matrix
Layer 1: validated self-report, ecological momentary assessment, contextual exposure, expectation, perceived control, social/environmental measures.
Layer 2: appropriately validated neural, autonomic, respiratory, sleep, sensory, behavioral-state, or neuroendocrine-control measures.
Layer 3: direct metabolic/endocrine assays, glucose/metabolic dynamics, circadian phase/timing, resource-related physiological measures.
Layer 4: movement, gait, balance, strength, range, breathing mechanics, mechanical loading, tissue properties, validated function.
Layer 5: direct laboratory, cellular, molecular, biochemical, immunologic, transcriptomic, proteomic, metabolomic, or other justified assays.
22. What the Five Layers Do Not Mean
They are not five anatomical systems.
They are not a ladder from spiritual to physical or from important to unimportant.
They do not imply that Layer 1 controls Layer 5.
They do not imply that every wellness intervention acts across all five layers.
They do not permit cellular or endocrine claims from subjective outcomes.
They do not require every study to measure all five layers.
They do not constitute a diagnosis, disease classification, or treatment plan.
23. Incremental-Value and Parsimony Test
The five-layer architecture should be retained only if it improves variable classification, reduces category errors, generates clearer hypotheses, improves interdisciplinary communication, or adds predictive value. More layers are not inherently more scientific. A simpler architecture should be preferred if it performs as well or better.
24. Canonical Public Definition
The CRF five layers are an organizing map for studying human regulation across Meaning & Context, Nervous System Regulation, Metabolic & Endocrine Coordination, Structural & Tissue Organization, and Cellular & Biochemical Function. They are research categories, not five newly discovered body systems, and claims must remain at the level actually measured.
25. Updated Falsification Commitments
If independent experts cannot assign representative variables to the layers with acceptable agreement, revise the boundaries.
If the architecture produces persistent ambiguity that does not improve with operational definitions, simplify it.
If alternative multilevel frameworks consistently outperform CRF in prediction or usability, prefer the alternative.
If adding layers increases model complexity without out-of-sample benefit, reject the added complexity.
If cross-layer claims cannot survive temporal alignment, confounder control, and replication, downgrade those claims.
26. Conclusion
The Five Layers of Human Regulation provide CRF with a disciplined multilevel map: Meaning & Context; Nervous System Regulation; Metabolic & Endocrine Coordination; Structural & Tissue Organization; and Cellular & Biochemical Function. Established science supports many processes within and between these domains, including context-sensitive stress regulation, allostatic and interoceptive control, circadian-metabolic timing, and reciprocal cell-matrix mechanotransduction. These literatures make a multilevel architecture plausible but do not validate the CRF arrangement.
The value of the five layers will depend on whether they improve measurement, prevent category errors, generate useful hypotheses, and add predictive value beyond simpler frameworks. Their most immediate contribution is therefore methodological: they require investigators and practitioners to state what was actually observed, what level a claim belongs to, and what additional evidence would be required to move from observation to mechanism.
Declarations
Author and originator: David Fischer. Institutional affiliation: Institute for Coherence and Regulation (ICR), Knightdale, North Carolina, USA.
Competing interests: The author is associated with an organization that develops educational materials, practitioner training, and wellness services related to CRF. Future empirical work should provide study-specific conflict-of-interest disclosures.
Ethics: This conceptual white paper reports no human-subject research. Data availability: No dataset was generated.
Canonical designation: ICR-WP-003, Publication Version 1.0, September 2026.
Version note: Publication Version 1.0 aligns the five-layer architecture with canonical WP-001 and WP-025, explicitly distinguishes layers from dynamic CRF constructs, strengthens the layer-assignment and cross-layer evidence rules, and adds a novelty/parsimony test against established multilevel frameworks.
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Appendix A — Canonical Layer Assignment Rule
Assign a variable to the layer represented by the measurement itself, not by the mechanism presumed to cause it. For example, perceived stress is Layer 1 even if it is hypothesized to influence autonomic physiology; heart rate is Layer 2 even if it is influenced by metabolism; meal timing is Layer 3 even if it is behaviorally chosen; gait is Layer 4 even if pain or neural control affects it; and an inflammatory biomarker is Layer 5 even if psychosocial stress is hypothesized to influence it.
Appendix B — Minimum Cross-Layer Claim Template
Source variable and CRF layer:
Target variable and CRF layer:
Proposed direction of influence:
Expected time scale or latency:
Candidate mechanism:
Alternative explanations/confounders:
Measurement method for each variable:
Evidence level: conceptual, observational, associational, comparative, mechanistic, or replicated.
Result that would count against the hypothesis: